Combinatorial methods have made an important impact on catalyst discovery in recent years. Notable examples include the discovery of catalysts for asymmetric acylation and Stetter-type chemistry, Pd(0) and Cu(I)-mediated allylic alkylations, Ag-based carbene insertion, FeCl2-mediated epoxidation, and early transition metal-based additions to imines. These successes have spurred interest in catalyst screening. Thus, screens for active lead catalysts, based upon IR thermography fluorescence and dye formation/bleaching have been reported. However, some methods for estimating relative rates, for example, involve the alteration of the substrate by the installation of a chromophore. In some cases, the substrate is so significantly altered, that a positive result in the screen, does not translate into a positive result with the original, unperturbed substrate.
Particularly valuable screens also provide information on enantioselectivity. Such screening methods include chiral GC and HPLC, CD and ORD and methods based upon installing MS or fluorescence tags or condensations with indicators.
The most common methods for estimating enantioselectivity are time-consuming and serial in nature. They involve chiral chromatography (usually HPLC or GC), and can be automated by the use of auto-injectors, but have the disadvantages of (i) requiring reaction quenching and work-up and of (ii) offering little possibility for parallel screening. Other approaches to estimating enantiomeric excess require that the product be derivatized, in a separate kinetic resolution step, following work-up of the reaction.
A reported in sits screen that provides information on both relative rate and product ee employs an isotopically chiral 13C NMR probe substrate. This allows obtaining information on both relative rate and enantioselectivity of the catalyst being screened, on the fly, without the need to draw aliquots. The disadvantage of that method is that it requires the stereoselective synthesis of an expensive 13-C-enriched model substrate. Furthermore, this approach placed the isotopically chiral, geminal dimethyl ‘reporting group’ directly adjacent to the carbonyl reaction center, thereby creating steric hindrance. This limits the suitability of the model substrate to mimic more common substrates for carbonyl addition reactions that possess sterically less hindered carbonyl groups.
As described in U.S. Pat. No. 6,974,665, the entire disclosure of which is incorporated herein by reference, enzymes can be used to assist organic chemists, using an approach termed “in situ enzymatic screening” (ISES). Enzymes are used to monitor relative rates in real time for allylic substitution catalysts run in parallel. ISES (In Situ Enzymatic Screening) is run in a bilayer, in this case, with a lower, aqueous enzymatic layer (containing ethanol dehydrogenase and aldehyde dehydrogenase) reporting (via NADH production) on the turnover of an allylic ethyl carbonate substrate in an upper organic reaction layer. The first examples of asymmetric, Ni(0)-mediated allylic amination reactions were uncovered in the process.